Abstract
Glucocorticoids exert their effects in target tissues predominantly through their interaction with the glucocorticoid receptor, a member of the nuclear receptor superfamily of transcription factors. Over the years many studies have linked hormone responsiveness, both in vitro and in vivo, to the levels of both glucocorticoid and glucocorticoid receptor; furthermore, an impact of glucocorticoid receptor subcellular trafficking on hormone response has been revealed. This review will focus on the molecular mechanisms responsible for the regulation of glucocorticoid receptor trafficking and expression, and will highlight work that revealed selective physiological effects of altered glucocorticoid receptor expression. The role of alterations in glucocorticoid levels and glucocorticoid receptor function in the metabolic syndrome will also be discussed.
Key Points
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The glucocorticoid receptor shuttles between the nuclear and cytoplasmic compartments and uses distinct transport proteins for this trafficking
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Degradation of glucocorticoid receptor protein by the ubiquitin–proteasome protein degradation system influences the steady-state level of receptor protein, and can be stimulated in some cells by hormone binding to the receptor
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The absolute level of glucocorticoid receptor protein expressed in a given cell can have a dramatic impact on cellular responsiveness to glucocorticoids, and can ultimately influence a wide range of physiological responses to glucocorticoids
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Accumulating data suggest that regulation of intracellular cortisol levels influences the pathogenesis of the metabolic syndrome
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Witchel, S., DeFranco, D. Mechanisms of Disease: regulation of glucocorticoid and receptor levels—impact on the metabolic syndrome. Nat Rev Endocrinol 2, 621–631 (2006). https://doi.org/10.1038/ncpendmet0323
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DOI: https://doi.org/10.1038/ncpendmet0323
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